(3R,4R)-pyrrolidine-3,4-diol

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 247.2, 300 mg, 0.654 mmol) and (3R,4R)-pyrrolidine-3,4-diol (88 mg, 0.850 mmol) in iPrOH (5 mL) was added DIPEA (0.228 mL, 1.307 mmol). The RM was stirred at 140° C. for 1 h and then 3 h at 130° C. The solvent was evaporated off under reduced pressure to give the crude product which was used directly without any further purification. UPLC-MS (Condition 3), tR=1.00 min, m/z=525.9/528.0 [M+H]+. 3 h at 130° C The solvent was evaporated off under reduced pressure

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 247.2, 300 mg, 0.654 mmol) and (3R,4R)-pyrrolidine-3,4-diol (88 mg, 0.850 mmol) in iPrOH (5 mL) was added DIPEA (0.228 mL, 1.307 mmol). The RM was stirred at 140° C. for 1 h and then 3 h at 130° C. The solvent was evaporated off under reduced pressure to give the crude product which was used directly without any further purification. UPLC-MS (Condition 3), tR=1.00 min, m/z=525.9/528.0 [M+H]+. 3 h at 130° C The solvent was evaporated off under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and (3R,4R)-pyrrolidine-3,4-diol by a procedure analogous to Example 1C. MS: 299.3/301.3 (MH+); HPLC Rf: 3.091 min.; HPLC purity: 99%.

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-chloro-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (61.0 mg, 0.20 mmol), (3R,4R)-3,4-dihydroxypyrrolidine (43 mg, 0.42 mmol) and triethylamine (0.055 mL, 0.42 mmol) in 3 mL of 2-propanol was heated in a sealed tube at 120° C. for 3 days. The temperature was raised to 150° C. After 3 days, additional portions of (3R,4R)-3,4-dihydroxypyrrolidine (40 mg) and triethylamine (0.055 mL) were added. After a total of 11 days, the solution was cooled and diluted with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, and dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by recrystallization from EtOAc/hexane (40 mg, 54%). Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C21H19FN3O3 (M+M+): 380.1405. Found 380.1401. After a total of 11 days, the solution was cooled The organic layer was washed with saturated NaHCO3 solution and brine dried over Na2SO4 filtered concentrated in vacuo The crude residue was purified by recrystallization from EtOAc/hexane (40 mg, 54%)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-chloro-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (61.0 mg, 0.20 mmol), (3R,4R)-3,4-dihydroxypyrrolidine (43 mg, 0.42 mmol) and triethylamine (0.055 mL, 0.42 mmol) in 3 mL of 2-propanol was heated in a sealed tube at 120° C. for 3 days. The temperature was raised to 150° C. After 3 days, additional portions of (3R,4R)-3,4-dihydroxypyrrolidine (40 mg) and triethylamine (0.055 mL) were added. After a total of 11 days, the solution was cooled and diluted with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, and dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by recrystallization from EtOAc/hexane (40 mg, 54%). Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C21H19FN3O3 (M+M+): 380.1405. Found 380.1401. After a total of 11 days, the solution was cooled The organic layer was washed with saturated NaHCO3 solution and brine dried over Na2SO4 filtered concentrated in vacuo The crude residue was purified by recrystallization from EtOAc/hexane (40 mg, 54%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (3R,4R)-3,4-dihydroxypyrrolidine in place of allylamine, the title compound was synthesized.

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 247.2, 300 mg, 0.654 mmol) and (3R,4R)-pyrrolidine-3,4-diol (88 mg, 0.850 mmol) in iPrOH (5 mL) was added DIPEA (0.228 mL, 1.307 mmol). The RM was stirred at 140° C. for 1 h and then 3 h at 130° C. The solvent was evaporated off under reduced pressure to give the crude product which was used directly without any further purification. UPLC-MS (Condition 3), tR=1.00 min, m/z=525.9/528.0 [M+H]+. 3 h at 130° C The solvent was evaporated off under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and (3R,4R)-pyrrolidine-3,4-diol by a procedure analogous to Example 1C. MS: 299.3/301.3 (MH+); HPLC Rf: 3.091 min.; HPLC purity: 99%.

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-chloro-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (61.0 mg, 0.20 mmol), (3R,4R)-3,4-dihydroxypyrrolidine (43 mg, 0.42 mmol) and triethylamine (0.055 mL, 0.42 mmol) in 3 mL of 2-propanol was heated in a sealed tube at 120° C. for 3 days. The temperature was raised to 150° C. After 3 days, additional portions of (3R,4R)-3,4-dihydroxypyrrolidine (40 mg) and triethylamine (0.055 mL) were added. After a total of 11 days, the solution was cooled and diluted with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, and dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by recrystallization from EtOAc/hexane (40 mg, 54%). Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C21H19FN3O3 (M+M+): 380.1405. Found 380.1401. After a total of 11 days, the solution was cooled The organic layer was washed with saturated NaHCO3 solution and brine dried over Na2SO4 filtered concentrated in vacuo The crude residue was purified by recrystallization from EtOAc/hexane (40 mg, 54%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (3R,4R)-3,4-dihydroxypyrrolidine in place of allylamine, the title compound was synthesized.